1. The molecular mechanism underlying long-term synaptic depression. The strength of synaptic transmission can change through synaptic plasticity. Long-lasting forms of synaptic plasticity (such as long-term potentiation and long-term depression of synaptic transmission) are important cellular mechanisms underlying information storage in the brain and the establishment of proper neural circuits during development. In this project, we investigated the mechanism underlying the induction of long-term depression of synaptic transmission (LTD). Our group has found that macroautophagy(autophagy hereinafter) plays an important role in LTD. Autophagy is a cellular process which mediates the degradation of cytoplasmic components and organelles via lysosomes. . Autophagy is also essential for the development and function of synapses. It enables developmental pruning of dendritic spines (subcellular structures accommodating postsynaptic components), and regulates presynaptic structure, dopamine release, and degradation of postsynaptic receptors. Anomalous autophagy is associated with brain disorders. Autophagy is orchestrated by more than 30 autophagy-related (Atg) proteins and multiple signaling pathways. Mechanistic target of rapamycin complex 1 (mTORC1) is the best-characterized regulator of autophagy induction in mammalian cells. Using mTOR inhibitors and knockout mice with deficient autophagy, we previously found that autophagic flux changes during LTD and this in turn leads to AMPA receptor endocytosis. During this reporting period, we investigated the mechanism by which autophagy regulates AMPA receptor internalization. We also examined the effect of altering autophagy on the behavior of mice. 2. The role of dysbindin-1 in synaptic physiology. Dysbindin-1 is a coiled-coil domain containing protein, initially discovered as a dystrophin-binding protein and later found to be one of eight subunits of biogenesis of lysosome-related organelles complex 1 (BLOC-1). The postmortem brains of individuals with schizophrenia consistently exhibit low levels of dysbindin-1 proteins and mRNAs. Our earlier work shows that dysbindin-1 contributes to the establishment of neuronal connectivity by regulating the growth of dendritic protrusions, including dendritic spines (tiny dendritic protrusions where excitatory synapses are formed) and filopodia (long, thin protrusions that serve as precursors of dendritic spines in young neurons). Dysbindin-1, therefore, may confer the risk for schizophrenia by regulating the development of dendritic spines. During this review period, we investigated the role of dysbindin-1 in psychogenic stress-induced synaptic alterations. We found that synaptic plasticity is more sensitive to psychogenic stress in dysbindin-1 mutant mice than in wild-type mice. Mild stress does not significantly affect synaptic plasticity in wild-type mice but alters social behavior in dysbindin-1 mutant mice. We recorded in the brain slice of stressed mice and found that stress alters synaptic physiology in mutant but not in wild-type mice. During this reporting period, we investigated the mechanism underlying this phenomenon and focused on determining the type of neurotransmitter receptors involved in psychogenic stress-induced synaptic alterations.